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Technology Development Unit

技术开发部

基本信息

批准号：
10539324
负责人：
Hao F Zhang
金额：
$ 86.51万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-10 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539324
关键词：
3-Dimensional Address Beds Behavior Budgets Cancer Biology Cell Nucleus Cell physiology Cells Chemoresistance Chromatin Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats Color Communities Computer Models Crowding DNA Data Development Diameter Electron Microscopy Ensure Epigenetic Process Etiology Family Feedback Gene Expression Genes Genetic Transcription Genome Mappings Genomics Goals Heterogeneity Image Label Link Location Longterm Follow-up Malignant Neoplasms Messenger RNA Methods Microscopy Modality Modeling Modification Molecular Molecular Analysis Molecular Computations Molecular Conformation Molecular Target Nucleosomes Optics Pattern Phenotype Photons Physics Polymers Population Preparation Process Quantum Dots Reaction Regulator Genes Research Research Personnel Resistance Resolution Sampling Scanning Techniques Technology Testing Therapeutic Time Tissues Transmission Electron Microscopy Universities Visualization Work anticancer research cancer cell cancer stem cell cellular imaging chemotherapy chromatin remodeling genome sequencing genomic locus histone modification imaging capabilities imaging platform improved light intensity meter microscopic imaging molecular dynamics molecular imaging molecular modeling molecular scale nano nanoassembly nanoimaging nanoscale nanosensors new technology next generation novel predictive modeling response role model sensor technology single molecule spatiotemporal spectroscopic imaging statistics stem success technology development theories three dimensional structure transcriptional reprogramming ultra high resolution

项目摘要

Technology Development Unit: PROJECT SUMMARY The overall goal of the U54 Northwestern University Center for Chromatin Nanoimaging in Cancer (NU-CCNIC) is to develop and deploy a multi-scale chromatin nanoimaging platform together with molecular analyses and computational modeling to characterize chromatin structure and transcriptional patterns associated with cancer stem cells (CSCs) and the chemoresistance phenotype. We seek to fill three technology gaps in developing such a nanoimaging platform. (1) The multi-scale challenge stems from the need to investigate how chromatin regulates gene expression across a wide range of scales, from the diameter of DNA (~2 nm) to the size of nucleosomes (~10 nm) to chromatin domains (~100 nm) to cell nuclei (~10 µm) and to a population of cells to account for intercellular heterogeneity. (2) The multiplexed molecular imaging challenge arises due to a large number of critical genes and molecular regulators that need to be co-registered with the 3D chromatin structural data. And (3) The temporal dynamics challenge requires the ability to work across a wide range of time scales to study short-term processes that may occur within minutes, such as chromatin remodeling, and long-term processes that may progress over weeks, such as the emergence of chemoresistance in cancer cells. No single technique satisfies all three requirements. Our solution to address these three challenges is to organically correlate three families of technologies: chromatin scanning transmission electron microscopy (ChromSTEM), spectroscopic single-molecule localization microscopy (sSMLM), and partial wave spectroscopic (PWS) nanosensing microscopy. After registering these technologies with 1 nm precision, they will collectively satisfy the multi-scale, multiplexing, and dynamics requirements. We will achieve three objectives in TECH. (1) Develop next-generation sSMLM that enables, in principle, unlimited multiplexing with the highest photon utilization and at 1 nm spatial precision. (2) Develop correlative ChromSTEM-sSMLM-PWS imaging that enables cross-modality registration at 1 nm precision assisted by novel quantum dot-based nano assembly fiduciary markers. And (3) Develop a multi-scale molecular modeling platform to elucidate the etiological relationship between chromatin structure and transcriptional reprogramming in CSCs imaged with the nanoimaging platform. The proposed technology development is driven by the needs of the Research Test-Bed unit (RTB) to elucidate epigenetic and chromatin drivers of transcriptional plasticity in CSC processes, in particular the development of adaptive resistance to chemotherapy, and to explore the feasibility of reprogramming CSCs out of the stem-states as a therapeutic strategy. Continuous feedback from RTB investigators will be integrated with the TECH platform's optimization, enabling, in the longer-term, our U54 technologies to impact the broader cancer research community within and beyond the Cellular Cancer Biology Imaging Research Network.

技术开发单位：项目总结